9-35675863-C-T

Variant names:

• chr9-35675863-C-T
• rs775729791
• NM_001216.3:c.536C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001216.3(CA9):​c.536C>T​(p.Pro179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CA9 NM_001216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 0 publications found

Genes affected

CA9 (HGNC:1383): (carbonic anhydrase 9) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]

ARHGEF39 (HGNC:25909): (Rho guanine nucleotide exchange factor 39) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell migration. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	NM_001216.3	MANE Select	c.536C>T	p.Pro179Leu	missense	Exon 3 of 11	NP_001207.2	Q16790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	ENST00000378357.9	TSL:1 MANE Select	c.536C>T	p.Pro179Leu	missense	Exon 3 of 11	ENSP00000367608.4	Q16790
	ARHGEF39	ENST00000490638.5	TSL:1	n.-2148G>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000436756.1	Q8N4T4-2
	ARHGEF39	ENST00000490638.5	TSL:1	n.-2148G>A		5_prime_UTR	Exon 1 of 12	ENSP00000436756.1	Q8N4T4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.71		Loss of disorder (P = 0.0165)
MVP		0.86
MPC		0.61
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.69
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775729791; hg19: chr9-35675860;